3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dione derivatives and compositions comprising and methods of using the same
Inventors
Assignees
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Publication Number
US-11040925-B2
Publication Date
2021-06-22
Expiration Date
Abstract
The invention provides 3-deuterium-enriched 3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treatment using the same, such as in the treatment of cancer, an immune-related disease, or an inflammatory disease.
Core Innovation
The invention concerns deuterium-enriched compounds of Formula I, including pharmaceutically acceptable salts, solvates, and stereoisomers thereof, in which Z is H or D provided that the abundance of deuterium in Z is at least 30%. The compounds allow multiple positions where substituents are selected from H and D, and the disclosure includes additional formula classes, alternative substituent definitions, and related enumerations, with any included H optionally replaced by D.
The disclosure additionally includes structural variants such as Formula IVa/IVb and related formula sets, together with isolated or purified deuterium-enriched compounds and mixtures of deuterated compounds. It emphasizes stereochemical control at the C—Z stereogenic carbon by requiring enantiomeric excess at defined levels, and extends the deuterium enrichment possibilities in Z to higher thresholds up to about 100%.
The document further extends the compounds to pharmaceutical compositions containing a pharmaceutically acceptable carrier and the claimed deuterium-enriched compound. The therapeutic use is framed through modulation of cytokines and angiogenesis, including effects on immune-related/lymphocytic activity, inflammatory disease, cancer, and cytokine-related disorders.
Claims Coverage
The claim coverage includes one main independent compound claim and dependent refinements that add quantitative deuterium and stereochemical constraints. Across the provided claims, the inventive content centers on deuterium enrichment at Z, enantiomeric excess relative to the C—Z carbon for selected formula branches, and a pharmaceutical composition containing the claimed compound.
Deuterium-enriched Formula I compounds with Z deuterium abundance at least 30%
A deuterium-enriched compound of Formula I, including pharmaceutically acceptable salts, solvates, and stereoisomers, wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%, and wherein specified substituent positions are independently selected from H and D or from enumerated substituent groups.
Enantiomeric excess relative to the C—Z carbon
Dependent claim coverage requires enantiomeric excess relative to the C—Z carbon at defined levels, including at least 5% in the provided branches, for Formula Ia/Ib, Formula IIa/IIb, and Formula IVa/IVb variants.
Higher deuterium abundance thresholds in Z
The claims further select deuterium abundance in Z at higher thresholds, including at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, or about 100%.
Pharmaceutical composition containing a claimed deuterium-enriched compound
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the claimed deuterium-enriched compound.
The claims center on deuterium-enriched Formula I compounds with a minimum deuterium abundance in Z of at least 30%, while further claim scope narrows structural variants, increases the deuterium-abundance thresholds, and imposes enantiomeric excess requirements relative to the C—Z carbon. Separate claim coverage also includes a pharmaceutical composition embodiment with a pharmaceutically acceptable carrier.
Stated Advantages
Resistance to racemization via stereochemical purity maintained through deuterium enrichment and stereochemical constraints.
Provides improved plasma stability as indicated by figure captions referencing plasma stability data.
Supports in vivo tumor-volume outcomes as indicated by figure captions referencing in vivo tumor-volume data.
Documented Applications
Therapeutic use is stated for cancer.
Therapeutic use is stated for immune-related/lymphocytic activity.
Therapeutic use is stated for inflammatory disease.
Therapeutic use is stated for angiogenesis and cytokine-related disorders.
Modulation of cytokines and angiogenesis, including cytokines TNF-α, IL-1β, IL-12, IL-18, GM-CSF, IL-6, IL-10, and IFN-γ.
Effects on natural killer (NK) cells and ADCC.
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